Case Study Shows Potential for CDK4/6 Inhibition in Metastatic Osteosarcoma

Margot A. Lazow, MD

The combination of gemcitabine and ribociclib (Kisqali) led to a radiographic and histologic response in a woman with chemotherapy-resistant metastatic CDK6-amplified osteosarcoma, according to a case study published in JCO Precision Oncology.

The patient experienced stable disease and significantly decreased fluorodeoxyglucose (FDG) avidity of the bilateral pulmonary nodules and pelvic mass on PET imaging after 6 cycles of therapy. Additionally, the woman experienced prolonged time to progression of 9 months, comparing favorably with historical rates ranging from 2 to 4 months in the relapsed/refractory setting.

“The present patient’s generally favorable radiographic and microscopic response provides an informative early experience using a small molecule inhibitor, targeting an amplified oncogene, in combination with a tolerable single-agent chemotherapy backbone,” Margot A. Lazow, MD, of Cincinnati Children’s Cancer and Blood Diseases Institute, and coinvestigators wrote.

The 26-year-old woman had presented with right hip pain and was found to have a greater than a 10-cm pelvic mass on CT with intra-articular hip involvement and pulmonary metastases. Hypermetabolic activity was shown on FDG-PET, and a biopsy of the pelvic mass confirmed highly aggressive and proliferative osteosarcoma.

The woman received standard cisplatin, doxorubicin, and high-dose methotrexate. She underwent a brain MRI after developing severe pain and neurologic events, which revealed a 0.45-cm lesion within the right frontal lobe. Subsequently, she underwent stereotactic radiosurgery at a dose of 20 Gy.

Radiologic assessment showed that the pulmonary nodules had increased in size and number after 2 cycles of treatment. Additionally, the woman had developed new right parietal leptomeningeal involvement, requiring another 20 Gy dose of stereotactic radiosurgery.

“This patient case presented a challenging combination of unfavorable prognostic factors, including older age, a pelvic primary tumor site, and an extraordinary extent of metastatic disease with innumerable lung nodules precluding surgical resection,” Lazow et al wrote.

Her rapid disease progression and treatment-related toxicity prompted investigators to seek alternative therapy. Next-generation sequencing of the pelvic mass revealed a CDK6 amplification (copy number = 11), AURKB amplification (copy number = 14), and TP53 truncation (of intron 9, with normal TP53 germline genetic testing).

The woman went on to receive 675 mg/m² of intravenous gemcitabine on days 1 and 8 and 400 mg of oral ribociclib on days 8 to 14 of every 21-day cycle. Ribociclib was ramped up to daily dosing after the first cycle. The woman went on to receive routine pegfilgrastim after showing evidence of mild neutropenia.

Ribociclib was selected among the other CDK4/6 inhibitors because of its increased penetration to the blood–brain barrier in glioblastoma xenografts, explained Lazow and coinvestigators.

After 6 cycles of treatment, investigators reported significant mineralization changes on chest CT and x-ray and no new pulmonary nodules. Brain MRI revealed less than 2 mm punctate focus of enhancement in the right parietal lobe next to the original radiation field, which resolved with a third dose of stereotactic radiosurgery.

After 9 cycles of treatment, a repeat biopsy of the pelvic mass revealed less proliferative residual disease and a significant phenotypic shift in cytologic and extracellular features.

“Although acknowledging that gemcitabine alone could be responsible for the treatment effect, we propose it is more plausible that the combination of agents was necessary to achieve the unique and favorable response in a tumor that previously progressed on cytotoxic chemotherapy,” Lazow et al wrote.

The combination was well tolerated until cycle 10, at which point the woman developed progressive lower extremity edema, which was attributed to gemcitabine. By cycle 11, the disease had progressed clinically and radiographically.

“Although the osteosarcoma genome generally lacks therapeutically targetable recurring point mutations, the exploitation of frequent somatic copy number aberrations or structural rearrangements may be deserving of broader investigation, especially among patients with metastatic and recurrent or refractory disease,”

Reference:

Lazow et al concluded.Lazow MA, Johnson SL, Johnson ND, et al. Genome-driven therapy for chemotherapy-resistant metastatic CDK6-amplified osteosarcoma. JCO Precis. 2020;498-504. doi:10.1200/PO.20.0003